The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerves of the patient, and more particularly to techniques for treating patients with diabetes and other systemic pancreatic disorders by application of such signals to a cranial nerve, using an implantable neurostimulating device, and specifically, by selective modulation of vagus nerve electrical activity.
Systemic disorders share a common pattern of multifocal or diffuse involvement of the nervous system including the cerebral hemispheres, the brain stem, the cerebellum, the spinal cord, the peripheral nerves and muscle. Among such disorders which are attributable to organ failure or disordered function, in contrast to those due to a specific pathological entity or pathological process, are the endocrine disorders. Disorders of the endocrine glands and neurological abnormalities may be linked in various clinical syndromes. Among the endocrine disorders are the pancreatic disorders of hypoglycemia and diabetes mellitus. Hypoglycemia is generally defined as a blood glucose concentration of less than 40 milligrams (mg) per 100 milliliters (ml) associated with suggestive signs and symptoms which vary with age and rapidity of onset of the hypoglycemia. The most common situation in which hypoglycemia occurs in humans is in the diabetic who is either taking insulin or a long-acting hypoglycemic agent. Typically, the diabetic is able to recognize the symptoms of hypoglycemia and to take the necessary action in avoidance (e.g., reduced dosage of insulin).
Diabetes is a condition characterized by excessive excretion of urine, either as a result of a deficiency of antidiuretic hormone (diabetes insipidus) or as a result of hyperglycemia, an abnormally high level of glucose in the blood (diabetes mellitus). The present invention is concerned primarily with treatment of diabetes mellitus, which is a complex disorder of carbohydrate, fat and protein metabolism primarily attributable to a relative or complete lack of insulin secretion by the beta cells of the pancreas or of defects of the insulin receptors, and a disease which is typically familial. Throughout the remainder of this specification and the claims, the term "diabetes" is intended to refer to diabetes mellitus.
Categories of diabetes specified by the National Institutes of Health include types I and II. Type I diabetes, formerly called juvenile-onset diabetes, includes patients who have abnormally low insulin levels and who are dependent upon insulin to prevent ketosis. If left untreated, ketosis can lead to ketoacidosis, coma, and death. Type II diabetes is non-insulin-dependent diabetes, and patients with this disease may have insulin levels which are normal or high, but decreased end organ sensitivity results in hyperglycemia. Neurological complications resulting from hyperglycemia can also progress to diabetic ketoacidosis, coma, and death. Other complications include peripheral neuropathy, mononeuritis multiplex, radiculopathy, autonomic neuropathy, cranial neuropathy, retinopathy, myelopathy, myopathy, nephropathy, teratogenicity, and premature atherosclerosis.
The goal of treatment of diabetes is to maintain insulin-glucose homeostasis, which may be controlled by diet alone in cases of mild early or late onset of the disease. In more severe cases, it is customary to administer a pharmacologic preparation of the insulin hormone to keep blood glucose levels below that where ketoacidosis is likely. Prescription insulin preparations vary in promptness, intensity, and duration of action, and may produce adverse reactions including hypoglycemia and insulin shock from excess dosage and hyperglycemia and diabetic ketoacidosis from inadequate dosage. Contraindications include possible adverse interaction with other drugs; increased insulin requirements in the presence of fever, stress and infection; allergic reactions to the insulin or components of the vehicle in which it is delivered; and decreased insulin requirements where liver or renal disease is present.
It is a principal object of the present invention to provide methods for treating diabetes by selectively increasing the secretion of insulin within the body whenever needed to maintain insulin-glucose homeostasis.
Normally, endogenous (naturally occurring) insulin hormone is secreted by the beta cells of islets in the pancreas in response to increased levels of glucose in the blood. As noted above, however, decreased end organ sensitivity can cause hyperglycemia even in individuals whose endogenous insulin levels are normal or even elevated. Moreover, blood glucose level is not the only stimulus for insulin secretion. The autonomic nervous system, through the vagus nerve, also affects insulin release (Rasmussen et al., Diabetic Care (1990) 13(6): 655-666). Daniel et al. reported in J. Physiol. (1967) 192: 317-327, finding a marked increase of pancreatic insulin release in baboons under vagal stimulation, but that hypoglycemia was not produced, possibly because of the low levels of stimulation.
A more specific object of the present invention is to apply techniques of selective modulation of the electrical activity of a cranial nerve of a patient, and particularly the vagus nerve, to increase or decrease the secretion of endogenous insulin, and thereby treat and control pancreatic disorders, particularly diabetes and hypoglycemia, respectively.
It is known that the nerves of the human body are generally composed of thousands of fibers of different sizes designated groups A B and C, which carry signals to and from the brain and other parts of the body. The vagus nerve, for example, may have approximately 100,000 fibers (axons) of the three different types, each of which carries such signals Each axon of that nerve only conducts in one direction, in normal circumstances. The A and B fibers are myelinated (i.e., each has a myelin sheath composed largely of fat), whereas the C fibers are unmyelinated. Typically, myelinated fibers are larger, conduct electrical signals faster, and are electrically stimulated at much lower thresholds than unmyelinated fibers. Such fibers exhibit a particular strength-duration curve in response to a specific width and amplitude of stimulation pulse.
The A and B fibers are stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. A fibers exhibit slightly faster electrical conductivities than the B fibers, and slightly lower electrical stimulation thresholds. The C fibers are relatively much smaller, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring wider pulse widths (e g., 300-1000 .mu.s) and higher amplitudes for activation. Although the A and B fibers may be selectively stimulated without also stimulating the C fibers, the magnitude and width of the pulse required for stimulating the C fibers would also activate A and B fibers.
Electrical stimulation of the nerve fiber typically activates neural signals in both directions (bidirectionally), but selective unidirectional stimulation is achievable through the use of special nerve electrodes and stimulating waveforms.
In a paper on the effects of vagal stimulation on experimentally induced seizures in rats (Eoilepsia (1990) 31 (Supp 2): S7-S19), Woodbury has noted that the vagus nerve is composed of somatic and visceral afferents (i.e., inward conducting nerve fibers which convey impulses toward a nerve center such as the brain or spinal cord) and efferents (i.e., outward conducting nerve fibers which convey impulses to an effector to stimulate it and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the neck. The central projections terminate largely in the nucleus of the solitary tract which sends fibers to various regions of the brain (e.g, the hypothalamus, thalamus, and amygdala); others continue to the medial reticular formation of the medulla, the cerebellum, the nucleus cuneatus and other regions.
Woodbury further notes that stimulation of vagal nerve afferent fibers in animals evokes detectable changes of the EEG in all of these regions, and that the nature and extent of these EEG changes depends on the stimulation parameters. Chase, in Exp Neurol (1966) 16:36-49, had also observed that vagal activation can affect the EEG activity of certain parts of the brain. Woodbury also observes that vagal stimulation can produce widespread inhibitory effects on seizures and certain involuntary movements.
Extra-physiologic electrical stimulation of the vagus nerve has previously been proposed for treatment of epilepsy and various forms of involuntary movement disorders. Specifically, in U.S. Pat. 4,702,254 to J. Zabara (referred to herein as "the '254 patent"), a method and implantable device are disclosed for alleviating or preventing epileptic seizures, characterized by abnormal neural discharge patterns of the brain. The '254 patent describes an implantable neurocybernetic prosthesis (NCP) which utilizes neurocybernetic spectral discrimination by tuning the external current of the NCP generator to the electrochemical properties of a specific group of inhibitory nerves that affect the reticular system of the brain. These nerves are embedded within a bundle of other nerves, and are selectively activated directly or indirectly by the tuning of the NCP to augment states of brain neural discharge to control convulsions or seizures. According to the patent, the spectral discrimination analysis dictates that certain electrical parameters of the NCP pulse generator be selected based on the electrochemical properties of the nerves desired to be activated. The patent further indicates that the optimum sites for application of the NCP generator output to produce the desired effects are the cranial nerves in general, and the vagus nerve in particular.
The NCP disclosed in the '254 patent may be activated manually or automatically to provide treatment for the duration of the seizure. Manual activation is performed when the patient experiences the aura at onset of the seizure. Alternatively, automatic activation may be triggered upon detection of instantaneous changes in certain state parameters immediately preceding or at onset of a seizure. Additionally, a prophylactic or preventive mode may be employed in which the NCP is activated periodically to reduce the occurrence and/or the intensity of the seizures. The NCP stimulator of the '254 patent is implanted in the patient's chest and is connected to electrodes installed at the selected point of signal application at the nerve site with the more negative electrode situated closer to the brain and the positive electrode further from the brain, along the vagus nerve.